Heat shock protein 90 (Hsp90) is a highly abundant mammalian protein, which is essential for cell viability and which exhibits dual chaperone functions. It plays a key role in the cellular stress-response by interacting with proteins after their native conformations have been altered by various environmental stresses, such as heat shock, thereby ensuring adequate protein-folding and preventing non-specific aggregation. Hsp90 may also play a role in buffering proteins against the effects of mutation, presumably by correcting the inappropriate folding of mutant proteins. Hsp90 also has an important regulatory role under normal physiological conditions and it is responsible for the conformational stability and maturation of a number of specific client proteins.
Hsp90 antagonists are currently being explored in a large number of biological contexts where a therapeutic effect may be obtained for a condition or disorder by inhibiting one or more aspects of Hsp90 activity. Although the primary focus of the research has been on proliferative disorders, such as cancers, other conditions have also been shown to be amenable to treatment using Hsp90 antagonists.
Geldanamycin is a macrocyclic lactam that is a member of the benzoquinone-containing ansamycin family of natural products. Geldanamycin's nanomolar potency and apparent selectivity for killing tumor cells, as well as the discovery that its primary target in mammalian cells is Hsp90, has stimulated interest in its development as an anti-cancer drug. However, the low solubility and association of hepatotoxicity with the administration of geldanamycin have led to difficulties in developing an appropriate composition for therapeutic applications. In particular, geldanamycin is poorly water soluble, making it difficult to deliver in therapeutically effective doses.
There have been considerable efforts to develop analogs of geldanamycin with reduced hepatotoxicity, increased aqueous solubility and comparable bioactivity. For example, geldanamycin analogs substituted at the 17-position with various amino groups (“17-amino-substituted geldanamycin analogs”) such as 17-AAG have shown reduced hepatotoxicity while maintaining Hsp90 binding but still suffer from low aqueous solubility (for example, see U.S. Pat. Nos. 4,261,989; 5,387,584; and 5,932,566). Examination of the corresponding hydroquinones has been limited as these compounds have generally been found to be unstable due to facile air oxidation (see Schnur et al., J. Med. Chem. (1995) 38:3813-3820 and Schnur et al., J. Med. Chem. (1995) 38:3806-3812).